CN104262327B - A kind of nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides and preparation method thereof and application - Google Patents

A kind of nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides and preparation method thereof and application Download PDF

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CN104262327B
CN104262327B CN201410503265.3A CN201410503265A CN104262327B CN 104262327 B CN104262327 B CN 104262327B CN 201410503265 A CN201410503265 A CN 201410503265A CN 104262327 B CN104262327 B CN 104262327B
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CN104262327A (en
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张晶珠
吴玖骏
章彬
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Shenzhen Kun Jian Original New Drug Research Institute
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

The invention provides nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in a kind of formula I or formula II and preparation method thereof and application.In formula I, formula II, R 1for H, OCH 3, OCH 2cH 3, OCH 2cH 2cH 3, Cl, Br, CF 3, NO 2or carbonatoms is the straight chained alkyl of 1-5, R 2for N (CH 3) 2or OCH 3, R 3for 2-pyridyl, 3-pyridyl, 4-pyridyl, indyl, quinolyl, pyrimidyl or pyrazinyl, m=1,2,3 or 4, n=1,2,3 or 4.Through kinds of tumor cells system, test (comprises liver cancer cell, leukemia cell etc.) and DNA connection, topoisomerase is tested, and proves that compound of the present invention is that a kind of potential DNA that has connects and topoisomerase had to the antitumor drug of inhibit activities.Raw materials of compound provided by the invention is easy to get, and preparation method is simple, and experiment proves that it has good anticancer effect, has good application prospect in antitumor drug design research and development field.

Description

A kind of nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides and preparation method thereof and application
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides and preparation method thereof and application.
Background technology
Cancer is one of overwhelming majority of countries and the highest factor of regional incidence of mortality in the world today, no matter developed country or developing country, the disease of cancer sends out rate and mortality ratio all creates very severe impact to the development of national economy and people's health care situation.So the cancer therapy drug researching and developing new and effective low toxicity is extremely urgent.Acridine and dihydroketoacridine structure are as one of small molecules parent nucleus important in medicament research and development, and three plane of a loop structures pi-conjugated in its structure, can intercalation of DNA double-strand, and suppresses DNA relevant enzyme, as topological enzyme and Telomerase.Existing many acridines and acridones compound enter clinical and preclinical phase in recent years.Therefore, acridine and dihydroketoacridine class formation are transformed and structure activity study, for research and development new type anticancer small-molecule drug highly significant.
Summary of the invention
An object of the present invention is to provide a kind of nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides.
Nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides provided by the present invention, its structural formula is such as formula shown in I or formula II:
In above-mentioned formula I, formula II, R 1for H, OCH 3, OCH 2cH 3, OCH 2cH 2cH 3, Cl, Br, CF 3, NO 2or carbonatoms is the straight chained alkyl of 1-5, R 2for N (CH 3) 2or OCH 3, R 3for 2-pyridyl, 3-pyridyl, 4-pyridyl, indyl, quinolyl, pyrimidyl or pyrazinyl, m=1,2,3 or 4, n=1,2,3 or 4.
Shown in above-mentioned formula I or formula II, compound pharmacy acceptable salt, ester or solvate also belong to protection scope of the present invention.
Wherein, described salt is inorganic acid salt or organic acid salt.
Described inorganic acid salt is selected from the salt that any one mineral acid following is formed: hydrochloric acid, sulfuric acid or phosphoric acid.
Described organic acid salt is selected from the salt that any one organic acid following is formed: acetic acid, trifluoroacetic acid, propanedioic acid, citric acid and tosic acid.
Nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in above-mentioned formula I or formula II be preferably following any one:
Nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in above-mentioned formula I or formula II prepares according to the method comprised the steps;
1) under condensing agent effect, the compound shown in the compound shown in formula III and formula IV is reacted, obtains the compound shown in formula V;
In formula III, R 1for H, OCH 3, OCH 2cH 3, OCH 2cH 2cH 3, Cl, Br, CF 3, NO 2or carbonatoms is the straight chained alkyl of 1-5;
In formula IV, R 2for N (CH 3) 2or OCH 3, n=1,2,3 or 4;
In formula V, R 1for H, OCH 3, OCH 2cH 3, OCH 2cH 2cH 3, Cl, Br, CF 3, NO 2or carbonatoms is the straight chained alkyl of 1-5, R 2for N (CH 3) 2or OCH 3, n=1,2,3 or 4;
2) under protection of inert gas, the compound shown in the compound shown in formula V and formula VI or the compound shown in formula VII are reacted, obtain the nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in formula I or formula II;
In formula VI, R 3for 2-pyridyl, 3-pyridyl, 4-pyridyl, indyl, quinolyl, pyrimidyl or pyrazinyl, m=1,2,3 or 4.
Aforesaid method step 1) in, described condensing agent is selected from following at least one: N, N'-carbonyl dimidazoles, dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide etc.
Compound shown in described formula IV be selected from following any one:
Described reaction is carried out in organic solvent, and described organic solvent is selected from following at least one: dimethyl formamide, N,N-DIMETHYLACETAMIDE, chloroform, methylene dichloride, acetone etc.
The mol ratio of the compound shown in the compound shown in described condensing agent and formula III, formula IV is followed successively by 1-4:1-2:1-10, specifically can be 2.61:1.74:5.22.
The temperature of reaction of described reaction is 20-40 DEG C, and the reaction times is 4-12 hour.
Aforesaid method step 2) in, described rare gas element is selected from following at least one: argon gas, nitrogen etc.
Compound shown in described formula VI be preferably following any one:
The proportioning of the compound shown in the compound shown in described formula V and formula VI or the compound shown in formula VII is 0.01-2mmol:0.5-5.00mL, specifically can be 0.28mmol:2.00mL.
The temperature of reaction of described reaction is 90-110 DEG C, and the reaction times is 10-20 hour.
Another object of the present invention is to provide the purposes of the nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in formula I or formula II and pharmacy acceptable salt, ester or solvate.
The application that the purposes of the nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in formula I provided by the present invention or formula II and pharmacy acceptable salt, ester or solvate is it in following:
1) application in topoisomerase enzyme inhibitor is being prepared;
2) application in preparation eukaryote tumor cell proliferation inhibitor;
3) application prevented and/or treated in tumour medicine is being prepared.
Described topoisomerase is topoisomerase I; Described eukaryote is Mammals; Described tumour cell is cancer cells; Described cancer cells is leukaemia cancer cell, lung carcinoma cell, human glioma cell, malignant melanoma cell, glioblastoma cells, cervical cancer cell, nasopharyngeal carcinoma cell, liver cancer cell, breast cancer cell, brain cancer cell, pancreatic cancer cell, ovarian cancer cell, uterine cancer cells, testicular cancer cell, skin cancer cell, stomach cancer cell, colon cancer cell, transitional cell bladder carcinoma cell line or rectum cancer cell.
Described leukaemia cancer cell is specially human chronic myelogenous leukemia (CML) cell line k562, described lung carcinoma cell is specially human lung carcinoma cell NCI-H520, described human glioma cell is specially U251, described malignant melanoma cell is specially A375, described glioblastoma cells is specifically people glioblastoma cells A172 and human brain astrocytes's blastoma cell U-118MG, described cervical cancer cell is specially Human cervical cancer cell lines Hela, described nasopharyngeal carcinoma cell is specially human nasopharyngeal epithelioma 1 CNE-2, described liver cancer cell is specially HepG2 cell lines, described breast cancer cell is specially human breast cancer cell line Bcap-37.
Described tumour is cancer; Described cancer is leukemia cancer, lung cancer, malignant melanoma, glioblastoma multiforme, cervical cancer, nasopharyngeal carcinoma, liver cancer, mammary cancer, the cancer of the brain, carcinoma of the pancreas, ovarian cancer, uterus carcinoma, carcinoma of testis, skin carcinoma, cancer of the stomach, colorectal carcinoma, bladder cancer or the rectum cancer.
The topoisomerase enzyme inhibitor being active fraction preparation with the nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in formula I or formula II and pharmacy acceptable salt, ester or solvate, eukaryote tumor cell proliferation inhibitor or the medicine preventing and/or treating tumour also belong to protection scope of the present invention.
Described topoisomerase enzyme inhibitor, eukaryote tumor cell proliferation inhibitor or the medicine that prevents and/or treats tumour import body as muscle, intracutaneous, subcutaneous, vein, mucosal tissue by the method for injection, injection, collunarium, eye drip, infiltration, absorption, physics or chemistry mediation; Or to be mixed by other materials or to import body after wrapping up.
When needing, one or more pharmaceutically acceptable carriers can also be added in said medicine.Described carrier comprises the thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant etc. of pharmaceutical field routine.
The topoisomerase enzyme inhibitor being active fraction preparation with the nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in formula I or formula II and pharmacy acceptable salt, ester or solvate, eukaryote tumor cell proliferation inhibitor or the medicine preventing and/or treating tumour can make the various ways such as injection liquid, tablet, pulvis, granule, capsule, oral liquid, paste, creme.The medicine of above-mentioned various formulation all can be prepared according to the ordinary method of pharmaceutical field.
Nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in formula I provided by the invention or formula II and pharmacy acceptable salt, ester or solvate, through kinds of tumor cells system, test (comprises liver cancer cell, leukemia cell etc.) and DNA connection, topoisomerase is tested, and proves that compound of the present invention is that a kind of potential DNA that has connects and topoisomerase had to the antitumor drug of inhibit activities.Raw materials of compound provided by the invention is easy to get, and preparation method is simple, and experiment proves that it has good anticancer effect, has good application prospect in antitumor drug design research and development field.
Accompanying drawing explanation
Fig. 1 is that compound 3 docks result figure with topoisomerase I-DNA mixture (PDBID:1K4T) molecular simulation, wherein, dihydroketoacridine parent in compound 3 structure and DNA base (DT10, TGP11, DC112 and DA113) form multiple π-π and interact.Compound 3 forms multiple hydrogen bond action with multiple amino-acid residues (ARG364, ARG488, LYS751, LYS532 and ASP533) of topological enzyme I in addition.
Fig. 2 is the detected through gel electrophoresis result figure of the suppression of compound shown in table 1 and table 2 topoisomerase I, wherein, Fig. 2 a is in embodiment 28, compound 1-15 suppresses the detected through gel electrophoresis result figure of topoisomerase I, Fig. 2 b is in embodiment 28, and compound 16-26 suppresses the detected through gel electrophoresis result figure of topoisomerase I.Wherein, Blank is blank, and DMSO is negative control.R and S represents DNA superhelix and relaxed state respectively.
Fig. 3 is that compound 3 is connected experimental result picture with DNA, wherein, Fig. 3 a is in embodiment 29, containing the absorbance measurement result of the solution to be measured of different concns ctDNA, Fig. 3 b is in embodiment 29, containing the fluorescent strength determining result of the solution to be measured of different concns ctDNA, Fig. 3 c is in embodiment 29, the fluorescent strength determining result that compound 3 and ethidium bromide (EB) are competed, Fig. 3 d is in embodiment 29, the viscosity measurements that compound 3 is combined with ctDNA.Wherein, Fig. 3 d X-coordinate represents the molar ratio of compound 3 and DNA, ordinate zou (η/η 0) 1/3for viscosity ratio, η is the viscosity of DNA when there is compound 3, η 0represent the viscosity number do not existed when compound 3 only has DNA.
Embodiment
Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.
The experimental technique used in following embodiment if no special instructions, is ordinary method; Reagent used in following embodiment, biomaterial etc., if no special instructions, all can obtain from commercial channels.
In this article, " shown in formula N compound ", sometimes also referred to as " compound N ", N is the arbitrary integer of 1-26 herein, and such as " shown in formula 3 compound " also can be called " compound 3 " in this article.
Embodiment 1: the preparation of (compound 1)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-tolyl acid is prepared
At dimethyl formamide (DMF, 2 are added 50.00ml), 4-dichlorobenzoic acid (0.61g, 4.05mmol), 2-amino-3-tolyl acid (0.79g, 5.26mmol), salt of wormwood (1.12g, 8.10mmol) with copper powder (0.13g, 2.03mmol), then stir at 130 DEG C and spend the night, then join in 200ml water after obtained reaction mixture being cooled, the mixture hydrochloric acid obtained is adjusted to pH value and is about 3, suction filtration by dry for the precipitation that obtains, obtain faint yellow solid, i.e. 2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-tolyl acid.Productive rate 91.5%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.10(s,2H),9.90(s,1H),7.86(d,J＝8.2Hz,1H),7.72(d,J＝7.2Hz,1H),7.56(t,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H),6.74(d,J＝7.5Hz,1H),6.08(s,1H),2.12(s,3H).
2, the chloro-5-methyl of 1--9-oxo-9,10-acridan-4-carboxylic acid is prepared
By 2-((2-carbonyl-5-chloro-phenyl-) the is amino)-3-tolyl acid (0.36g obtained in step 1,1.19mmol) join in the vitriol oil (10.00ml), in 80 DEG C of backflows 5 hours, then slowly join in frozen water (50mL) after obtained reaction solution being cooled, be adjusted to pH value by NaOH solution subsequently and be about 5, mixed solution continued stirring at room temperature after 30 minutes, had a large amount of Precipitation.Suction filtration also by dry for the precipitation obtained, obtains pressed powder, i.e. the chloro-5-methyl of 1--9-oxo-9,10-acridan-4-carboxylic acid.Productive rate 95.0%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ12.59(s,1H),8.32(d,J＝8.3Hz,1H),8.05(d,J＝8.0Hz,1H),7.66(d,J＝6.8Hz,1H),7.32(d,J＝8.3Hz,1H),7.24(dd,J＝7.9,7.3Hz,1H),2.54(s,3H).
3,1-chloro-N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By the chloro-5-methyl of the 1--9-oxo-9 obtained in step 2,10-acridan-4-carboxylic acid (1.0g, 3.48mmol) is slowly added dropwise to N, N '-carbonyl dimidazoles (0.85g, (DMF in dimethyl formamide solution 5.22mmol), 10.00ml), in stirring at room temperature 30 minutes after dropwising, then by N, N-dimethyl-1,2-quadrol (0.92g, 10.44mmol) adds in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, i.e. the chloro-N-of 1-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 65.3%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ12.93(s,1H),8.27(d,J＝8.0Hz,1H),7.72(d,J＝8.3Hz,1H),7.50(d,J＝7.0Hz,1H),7.19(t,J＝7.7Hz,1H),7.15(d,J＝8.1Hz,1H),3.57(dd,J＝10.9,5.3Hz,2H),2.64-2.59(m,2H),2.58(s,3H),2.33(s,6H).
4, the preparation of compound 1
By the chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-methyl-9-oxo-9 obtained in step 3; 10-dihydropyridine-4-acid amides (0.099g; 0.28mmol) be dissolved in 2-picolyl amine (2.00mL); reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 1 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 36.1%, fusing point 168-170 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+430.2243, experimental value: 430.2242.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.97(s,1H),11.39(t,J＝5.3Hz,1H),8.62(d,J＝4.2Hz,1H),8.41(t,J＝5.3Hz,1H),8.06(dd,J＝17.4,8.4Hz,2H),7.80(td,J＝7.7,1.7Hz,1H),7.60(d,J＝7.0Hz,1H),7.44(d,J＝7.8Hz,1H),7.33(dd,J＝6.7,5.1Hz,1H),7.19(t,J＝7.6Hz,1H),6.35(d,J＝9.0Hz,1H),4.71(d,J＝5.4Hz,2H),3.41(dd,J＝12.5,6.5Hz,2H),2.53(s,3H),2.49-2.42(m,2H),2.22(s,6H)； 13CNMR(100MHz,DMSO-d 6)δ180.28,169.33,157.84,154.40,149.67,144.58,138.46,137.44,135.09,134.16,125.18,123.78,122.93,122.10,121.77,121.54,106.33,101.52,100.46,58.61,48.19,45.69,37.60,17.02.
Embodiment 2: the preparation of (compound 2)
Prepare compound 2 according to the step of embodiment 1, difference is: change the 2-picolyl amine in the step 4 in embodiment 1 into 3-picolyl amine and react.The productive rate 36.1% of gained compound 2, fusing point 149-151 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+430.2243, experimental value: 430.2244.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.93(s,1H),11.22(t,J＝5.5Hz,1H),8.67(s,1H),8.57–8.42(m,2H),8.05(d,J＝8.6Hz,2H),7.82(d,J＝7.8Hz,1H),7.60(d,J＝6.9Hz,1H),7.40(dd,J＝7.6,4.9Hz,1H),7.19(t,J＝7.6Hz,1H),6.37(d,J＝9.0Hz,1H),4.67(d,J＝5.6Hz,2H),3.47-3.43(m,2H),2.70-2.60(m,2H),2.52(s,3H),2.32(s,6H). 13CNMR(100MHz,DMSO-d 6)δ180.43,169.42,154.51,149.40,148.95,144.53,138.45,135.57,135.21,134.56,134.23,125.18,124.19,123.74,121.83,121.47,106.30,101.76,100.35,58.27,45.22,43.81,37.15,16.95.
Embodiment 3: the preparation of (compound 3)
Prepare compound 3 according to the step of embodiment 1, difference is: change the 2-picolyl amine in the step 4 in embodiment 1 into 4-picolyl amine and react.The productive rate 59.4% of gained compound 3, fusing point 220-222 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+430.2243, experimental value: 430.2246.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.62(s,1H),11.53(t,J＝5.7Hz,1H),8.56(d,J＝5.3Hz,2H),8.25(d,J＝8.1Hz,1H),7.64(d,J＝8.9Hz,1H),7.50(d,J＝7.0Hz,1H),7.31(d,J＝5.2Hz,2H),7.19(t,J＝7.6Hz,1H),6.99(s,1H),6.03(d,J＝8.9Hz,1H),4.59(d,J＝6.0Hz,2H),3.52(dd,J＝10.7,5.2Hz,2H),2.63(s,3H),2.55(t,J＝5.7Hz,2H),2.28(s,6H)； 13CNMR(100MHz,CDCl 3)δ181.38,169.23,154.87,150.13,147.50,144.60,138.54,133.79,133.53,125.02,123.81,121.92,121.75,121.60,106.92,102.08,99.71,57.68,45.70,45.09,36.79,17.14.
Embodiment 4: the preparation of (compound 4)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-tolyl acid is prepared according to the step 1 in embodiment 1;
2, the chloro-5-methyl of 1--9-oxo-9,10-acridan-4-carboxylic acid is prepared according to the step 2 in embodiment 1;
3,1-chloro-N-(3-(dimethylamino) propyl group)-5-methyl-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By the chloro-5-methyl of the 1--9-oxo-9 obtained in step 2,10-acridan-4-carboxylic acid (0.5g, 1.74mmol) is slowly added dropwise to N, N '-carbonyl dimidazoles (0.42g, (DMF in dimethyl formamide solution 2.61mmol), 10.00ml), in stirring at room temperature 30 minutes after dropwising, then by N, N-dimethyl-1,3-propylene diamine (0.53g, 5.22mmol) adds in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, i.e. the chloro-N-of 1-(3-(dimethylamino) propyl group)-5-methyl-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 61.9%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.34(s,1H),9.65(s,1H),8.29(d,J＝8.1Hz,1H),7.65(d,J＝8.3Hz,1H),7.51(d,J＝7.1Hz,1H),7.21-7.15(m,2H),3.64(dd,J＝10.2,5.8Hz,2H),2.67-2.62(m,2H),2.61(s,3H),2.39(s,6H),1.85(dt,J＝11.4,5.8Hz,2H).
4, the preparation of compound 4
By the chloro-N-of 1-(3-(dimethylamino) the propyl group)-5-methyl-9-oxo-9 obtained in step 3; 10-dihydropyridine-4-acid amides (0.10g; 0.28mmol) be dissolved in 2-picolyl amine (2.00mL); reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 4 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 56.8%, fusing point 162-164 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+444.2400, experimental value: 444.2383.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.85(s,1H),11.61(t,J＝5.7Hz,1H),8.78(s,1H),8.64(d,J＝4.2Hz,1H),8.27(d,J＝8.0Hz,1H),7.65(td,J＝7.7,1.7Hz,1H),7.53(d,J＝8.9Hz,1H),7.49(d,J＝7.0Hz,1H),7.41(d,J＝7.9Hz,1H),7.20(dd,J＝8.0Hz,1H),7.16(t,J＝7.9Hz,1H),6.17(d,J＝8.9Hz,1H),4.72(d,J＝5.9Hz,2H),3.58(dd,J＝10.6,5.7Hz,2H),2.63(s,3H),2.57-2.45(m,2H),2.33(s,6H),1.79(dt,J＝11.6,5.9Hz,2H)； 13CNMR(100MHz,CDCl 3)δ181.35,169.37,158.16,154.86,149.47,144.78,138.64,136.96,133.59,133.26,125.02,123.87,122.24,121.78,121.34,121.09,106.98,101.97,99.94,59.59,48.66,45.41,40.69,24.83,17.23.
Embodiment 5: the preparation of (compound 5)
Prepare compound 5 according to the step of embodiment 4, difference is: change the 2-picolyl amine in the step 4 in embodiment 4 into 3-picolyl amine and react.The productive rate 56.2% of gained compound 5, fusing point 143-145 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+444.2400, experimental value: 444.2405.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.86(s,1H),11.45(t,J＝5.6Hz,1H),8.80(s,1H),8.67(d,J＝1.7Hz,1H),8.54(dd,J＝4.8,1.4Hz,1H),8.22(d,J＝8.1Hz,1H),7.75(d,J＝7.9Hz,1H),7.58(d,J＝8.9Hz,1H),7.49(d,J＝7.0Hz,1H),7.32-7.28(m,1H),7.17(t,J＝7.6Hz,1H),6.14(d,J＝8.9Hz,1H),4.60(d,J＝5.7Hz,2H),3.59(dd,J＝10.7,5.6Hz,2H),2.63(s,3H),2.61-2.56(m,2H),2.37(s,6H),1.89-1.74(m,2H)； 13CNMR(100MHz,CDCl 3)δ181.34,169.33,154.71,149.00,148.84,144.74,138.61,134.81,133.71,133.66,133.33,125.05,123.75,121.73,121.43,106.92,102.22,99.58,59.29,45.26,44.31,40.37,24.80,17.18.
Embodiment 6: the preparation of (compound 6)
Prepare compound 6 according to the step of embodiment 4, difference is: change the 2-picolyl amine in the step 4 in embodiment 4 into 4-picolyl amine and react.The productive rate 36.7% of gained compound 6, fusing point 199-201 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+444.2400, experimental value: 444.2397.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.89(s,1H),11.53(s,1H),8.85(s,1H),8.57(d,J＝4.2Hz,2H),8.25(d,J＝7.6Hz,1H),7.52-7.50(m,2H),7.33(d,J＝3.7Hz,2H),7.18(t,J＝7.3Hz,1H),6.03(d,J＝8.8Hz,1H),4.61(d,J＝5.3Hz,2H),3.60-3.50(m,2H),2.64(s,3H),2.55-2.45(m,2H),2.33(s,6H),1.80-1.70(m,2H)； 13CNMR(100MHz,CDCl 3)δ181.44,169.26,154.74,150.21,147.49,144.75,138.66,133.75,133.21,125.13,123.81,121.95,121.74,121.51,106.99,102.47,99.60,59.69,45.70,45.45,40.81,24.75,17.24.
Embodiment 7: the preparation of (compound 7)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-tolyl acid is prepared according to the step 1 in embodiment 1;
2, the chloro-5-methyl of 1--9-oxo-9,10-acridan-4-carboxylic acid is prepared according to the step 2 in embodiment 1;
3,1-chloro-N-(2-methoxy ethyl)-5-methyl-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By the chloro-5-methyl of the 1--9-oxo-9 obtained in step 2,10-acridan-4-carboxylic acid (0.5g, 1.74mmol) be slowly added dropwise to N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (0.42g, 2.61mmol) (DMF, 10.00ml), in stirring at room temperature 30 minutes after dropwising, then 2-methoxyethyl amine (0.39g, 5.22mmol) is added in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, i.e. the chloro-N-of 1-(2-methoxy ethyl)-5-methyl-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 61.9%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ12.79(s,1H),8.27(d,J＝8.1Hz,1H),7.72(d,J＝8.2Hz,1H),7.51(d,J＝7.0Hz,1H),7.19(t,J＝7.6Hz,1H),7.14(d,J＝8.2Hz,1H),6.90(s,1H),3.74(dd,J＝9.7,4.8Hz,2H),3.65(t,J＝4.8Hz,2H),3.45(s,3H),2.58(s,3H).
4, the preparation of compound 7
By the chloro-N-of 1-(2-the methoxy ethyl)-5-methyl-9-oxo-9 obtained in step 3; 10-dihydropyridine-4-acid amides (0.096g; 0.28mmol) be dissolved in 2-picolyl amine (2.00mL), reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 7 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 57.9%, fusing point 206-207 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+417.1927, experimental value: 417.1927.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.49(s,1H),11.65(s,1H),8.65(d,J＝4.2Hz,1H),8.27(d,J＝8.1Hz,1H),7.66(td,J＝7.8,1.5Hz,1H),7.61(d,J＝8.9Hz,1H),7.50(d,J＝6.9Hz,1H),7.40(d,J＝7.8Hz,1H),7.20(dt,J＝15.1,7.5Hz,2H),6.56(s,1H),6.17(d,J＝8.9Hz,1H),4.73(d,J＝5.7Hz,2H),3.67(dd,J＝9.7,4.8Hz,2H),3.62-3.53(m,2H),3.41(s,3H),2.62(s,3H)； 13CNMR(100MHz,CDCl 3)δ181.28,169.29,157.95,155.13,149.46,144.68,138.50,137.01,133.68,133.33,124.92,123.92,122.30,121.85,121.51,121.12,106.92,101.49,100.00,71.26,58.90,48.63,39.41,17.14.
Embodiment 8: the preparation of (compound 8)
Prepare compound 8 according to the step of embodiment 7, difference is: change the 2-picolyl amine in the step 4 in embodiment 7 into 3-picolyl amine and react.The productive rate 57.9% of gained compound 8, fusing point 184-185 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+417.1927, experimental value: 417.1920.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.51(s,1H),11.50(t,J＝5.5Hz,1H),8.67(d,J＝1.7Hz,1H)，8.55(dd，J＝4.8，1.4Hz，1H)，8.23(d，J＝8.1Hz，1H)，7.74(d，J＝7.8Hz，1H)，7.61(d,J＝8.9Hz,1H),7.50(d,J＝7.0Hz,1H),7.31-7.28(m,1H),7.19(t,J＝7.6Hz,1H),6.54(s,1H),6.14(d,J＝8.9Hz,1H),4.60(d,J＝5.7Hz,2H),3.67(dd,J＝9.9,4.8Hz,2H),3.59(t,J＝4.8Hz,2H),3.41(s,3H),2.62(s,3H)； 13CNMR(100MHz,CDCl 3)δ181.31,169.21,154.96,149.01,148.90,144.64,138.49,134.80,133.78,133.58,133.33,124.97,123.81,123.76,121.79,121.63,106.88,101.76,99.65,71.22,58.90,44.34,39.41,17.12.
Embodiment 9: the preparation of (compound 9)
Prepare compound 9 according to the step of embodiment 7, difference is: change the 2-picolyl amine in the step 4 in embodiment 7 into 4-picolyl amine and react.The productive rate 82.7% of gained compound 9, fusing point 228-230 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+417.1927, experimental value: 417.1932.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.53(s,1H),11.59(s,1H),8.59(d,J＝4.7Hz,2H),8.27(d,J＝8.1Hz,1H),7.60(d,J＝8.8Hz,1H),7.53(d,J＝7.0Hz,1H),7.33(d,J＝4.5Hz,2H),7.22(t,J＝7.6Hz,1H),6.51(s,1H),6.05(d,J＝8.9Hz,1H),4.62(d,J＝5.7Hz,2H),3.68(d,J＝4.7Hz,2H),3.60(d,J＝4.5Hz,2H),3.41(s,3H),2.64(s,3H)； 13CNMR(100MHz,CDCl 3)δ181.39,169.17,155.02,150.17,147.42,144.64,138.52,133.86,133.29,125.01,123.85,121.93,121.80,121.69,106.94,101.95,99.72,71.18,58.90,45.72,39.41,17.13.
Embodiment 10: the preparation of (compound 10)
Compound 10 is prepared according to the step of embodiment 7, difference is: the 2-picolyl amine in the step 4 in embodiment 7 is changed into two (2-pyridyl) methylamine and react, the productive rate 33.9% of gained compound 10, fusing point 180-182 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+508.2349, experimental value: 508.2363.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.21(s,1H),8.48(d,J＝4.5Hz,2H),8.28(d,J＝8.0Hz,1H),7.63(d,J＝8.8Hz,1H),7.61-7.50(m,4H),7.48(d,J＝6.9Hz,1H),7.17(t,J＝7.6Hz,1H),7.10(t,J＝6.0Hz,,2H),6.87(s,1H),6.58(d,J＝8.8Hz,1H),4.73(s,4H),3.65(dd,J＝9.8,4.8Hz,2H),3.60-3.46(m,2H),3.37(s,3H),2.61(s,3H)； 13CNMR(100MHz,CDCl 3)δ178.11,169.07,158.36,155.02,149.02,145.36,138.15,136.77,133.44,131.57,124.59,122.94,122.77,122.06,121.35,112.39,109.11,106.93,71.13,59.78,58.83,39.49,17.02.
Embodiment 11: the preparation of (compound 11)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-methoxybenzoic acid is prepared
At dimethyl formamide (DMF, 2 are added 50.00ml), 4-dichlorobenzoic acid (0.61g, 4.05mmol), 2-amino-3-methoxybenzoic acid (0.88g, 5.26mmol), salt of wormwood (1.12g, 8.10mmol) with copper powder (0.13g, 2.03mmol), then stir at 130 DEG C and spend the night, then join in 200ml water after obtained reaction mixture being cooled, the mixture hydrochloric acid obtained is adjusted to pH value and is about 3, suction filtration by dry for the precipitation that obtains, obtain faint yellow solid, i.e. 2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-tolyl acid.Productive rate 98.9%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.12(s,2H),10.07(s,1H),7.85(d,J＝5.4Hz,1H),7.48(d,J＝5.2Hz,1H),7.41-7.21(m,2H),6.76(d,J＝5.4Hz,1H),6.28(s,1H),3.79(s,3H).
2,1-chloro-5-methoxyl-9-oxo-9,10-acridan-4-carboxylic acid is prepared
By 2-((2-carbonyl-5-chloro-phenyl-) the is amino)-3-methoxybenzoic acid (0.38g obtained in step 1,1.19mmol) join in the vitriol oil (10.00ml), in 80 DEG C of backflows 5 hours, then slowly join in frozen water (50mL) after obtained reaction solution being cooled, be adjusted to pH value by NaOH solution subsequently and be about 5, mixed solution continued stirring at room temperature after 30 minutes, had a large amount of Precipitation.Suction filtration also by dry for the precipitation obtained, obtains pressed powder, i.e. 1-chloro-5-methoxyl-9-oxo-9,10-acridan-4-carboxylic acid.Productive rate 92.7%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.97(s,1H),12.56(s,1H),8.26(d,J＝8.2Hz,1H),7.70(d,J＝8.1Hz,1H),7.34(d,J＝7.8Hz,1H),7.28(d,J＝8.2Hz,1H),7.22(t,J＝7.9Hz,1H),4.02(s,3H).
3,1-chloro-N-(2-(dimethylamino) ethyl)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By the 1-chloro-5-methoxyl-9-oxo-9 obtained in step 2,10-acridan-4-carboxylic acid (0.5g, 1.65mmol) is slowly added dropwise to N, N '-carbonyl dimidazoles (0.40g, (DMF in dimethyl formamide solution 2.48mmol), 10.00ml), in stirring at room temperature 30 minutes after dropwising, then by N, N-dimethyl-1,2-quadrol (0.44g, 4.95mmol) adds in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, i.e. the chloro-N-of 1-(2-(dimethylamino) ethyl)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 58.7%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ12.90(s,1H),7.97(dd,J＝8.2,0.9Hz,1H),7.75(d,J＝8.2Hz,1H),7.19(dt,J＝8.1,3.8Hz,2H),7.11(dd,J＝7.8,1.1Hz,1H),4.08(s,3H),3.60(dd,J＝11.2,5.0Hz,2H),2.65-2.56(m,2H),2.32(s,6H)； 13CNMR(100MHz,DMSO-d 6)δ176.02,168.82,155.70,147.73,144.89,132.92,130.22,123.41,121.16,117.57,112.37,109.91,105.48,104.58,58.68,56.80,45.76,43.80,37.73.
4, the preparation of compound 11
By the chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-methoxyl group-9-oxo-9 obtained in step 3; 10-dihydropyridine-4-acid amides (0.10g; 0.28mmol) be dissolved in 2-picolyl amine (2.00mL); reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 11 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 41.9%, fusing point 201-203 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+446.2192, experimental value: 446.2190.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.60(s,1H),11.64(s,1H),8.65-8.64(m,1H),7.97(d,J＝8.0Hz,1H),7.68-7.64(m,2H),7.41(d,J＝7.6Hz,1H),7.19(d,J＝7.8Hz,2H),7.10(d,J＝7.4Hz,1H),6.97(s,1H),6.18(d,J＝8.8Hz,1H),4.73(d,J＝5.7Hz,2H),4.10(s,3H),3.56(d,J＝4.9Hz,2H),2.74-2.46(m,2H),2.31(s,6H)； 13CNMR(100MHz,CDCl 3)δ180.91,169.09,158.11,155.09,149.51,147.94,144.15,136.93,133.65,131.02,122.46,122.23,121.15,121.05,117.17,111.31,107.37,102.06,99.94,57.76,56.28,48.70,45.08,36.73.
Embodiment 12: the preparation of (compound 12)
Prepare compound 12 according to the step of embodiment 11, difference is: change the 2-picolyl amine in the step 4 in embodiment 11 into 3-picolyl amine and react.The productive rate 53.9% of gained compound 12, fusing point 222-224 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+446.2192, experimental value: 446.2207.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.83(s,1H),11.21(t,J＝5.7Hz,1H),8.66(s,1H),8.50(d,J＝4.6Hz,1H),8.31(s,1H),8.00(d,J＝8.9Hz,1H),7.82(d,J＝7.6Hz,1H),7.75(d,J＝8.1Hz,1H),7.40(dd,J＝7.6,4.9Hz,1H),7.31(d,J＝7.8Hz,1H),7.20(t,J＝8.0Hz,1H),6.36(d,J＝8.9Hz,1H),4.66(d,J＝5.7Hz,2H),4.04(s,3H),3.41-3.38(m,2H),2.43(t,J＝6.8Hz,2H),2.19(s,6H)； 13CNMR(100MHz,DMSO-d 6)δ180.05,168.87,154.45,149.40,148.93,147.94,143.94,135.57,135.12,134.59,130.71,124.18,122.05,121.80,116.95,112.84,106.73,102.30,100.25,58.69,56.88,45.77,43.83,37.72.
Embodiment 13: the preparation of (compound 13)
Prepare compound 13 according to the step of embodiment 11, difference is: change the 2-picolyl amine in the step 4 in embodiment 11 into 4-picolyl amine and react.The productive rate 83.8% of gained compound 13, fusing point 190-192 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+446.2192, experimental value: 446.2209.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.61(s,1H),11.54(s,1H),8.57(d,J＝4.8Hz,2H),7.95(d,J＝8.2Hz,1H),7.69(d,J＝8.9Hz,1H),7.32(d,J＝5.2Hz,2H),7.21(t,J＝8.0Hz,1H),7.12(t,J＝7.0Hz,1H),7.08(s,1H),6.03(d,J＝8.8Hz,1H),4.59(d,J＝5.9Hz,2H),4.10(s,3H),3.58(dd,J＝10.5,5.1Hz,2H),2.62(t,J＝5.6Hz,2H),2.34(s,6H)； 13CNMR(100MHz,CDCl 3)δ180.98,169.02,154.92,150.15,147.96,147.50,144.07,133.70,131.02,122.38,121.94,121.33,117.07,111.44,102.50,100.00,99.69,57.82,56.30,45.73,45.00,36.63.
Embodiment 14: the preparation of (compound 14)
Compound 14 is prepared according to the step of embodiment 11, difference is: the 2-picolyl amine in the step 4 in embodiment 11 is changed into two (2-pyridyl) methylamine and react, the productive rate 38.7% of gained compound 14, fusing point 97-98 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+537.2614, experimental value: 537.2595.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.26(s,1H),8.48(d,J＝4.6Hz,2H),7.97(d,J＝7.9Hz,1H),7.76-7.66(m,1H),7.60-7.52(m,4H),7.25(s,1H),7.17(t,J＝8.0Hz,1H),7.10-7.07(m,3H),6.63(d,J＝8.8Hz,1H),4.73(s,4H),4.08(s,3H),3.60(dd,J＝10.8,5.2Hz,2H),2.64(t,J＝5.6Hz,2H),2.36(s,6H)； 13CNMR(100MHz,CDCl 3)δ177.66,168.83,158.40,154.94,149.05,147.80,144.85,136.81,131.95,130.58,123.47,122.77,122.06,120.98,117.85,112.73,111.25,109.16,107.39,60.43,59.81,57.86,56.28,44.96,36.57.
Embodiment 15: the preparation of (compound 15)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-methoxybenzoic acid is prepared according to step 1 in embodiment 11;
2,1-chloro-5-methoxyl-9-oxo-9,10-acridan-4-carboxylic acid is prepared according to step 2 in embodiment 11;
3,1-chloro-N-(3-(dimethylamino) propyl group)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By the 1-chloro-5-methoxyl-9-oxo-9 obtained in step 2,10-acridan-4-carboxylic acid (0.5g, 1.65mmol) is slowly added dropwise to N, N '-carbonyl dimidazoles (0.40g, (DMF in dimethyl formamide solution 2.48mmol), 10.00ml), in stirring at room temperature 30 minutes after dropwising, then by N, N-dimethyl-1,3-propylene diamine (0.53g, 5.22mmol) adds in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, i.e. the chloro-N-of 1-(3-(dimethylamino) propyl group)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 60.5%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.27(s,1H),9.51(s,1H),7.97(d,J＝8.4Hz,1H),7.63(d,J＝8.3Hz,1H),7.18(t,J＝8.4Hz,1H),7.17(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),4.08(s,3H),3.65(dd,J＝10.0,5.7Hz,2H),2.69–2.57(m,2H),2.36(s,6H),1.83(dt,J＝11.3,5.8Hz,2H).
4, the preparation of compound 15
By the chloro-N-of 1-(3-(dimethylamino) the propyl group)-5-methoxyl group-9-oxo-9 obtained in step 3; 10-dihydropyridine-4-acid amides (0.11g; 0.28mmol) be dissolved in 2-picolyl amine (2.00mL); reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 15 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 67.4%, fusing point 204-206 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+460.2349, experimental value: 460.2343.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.87(s,1H),11.53(t,J＝5.8Hz,1H),8.76(s,1H),8.57(dd,J＝4.5,1.5Hz,2H),7.94(d,J＝7.9Hz,1H),7.52(d,J＝8.9Hz,1H),7.33(d,J＝5.9Hz,2H),7.19(t,J＝8.0Hz,1H),7.09(dd,J＝7.8,0.9Hz,1H),6.02(d,J＝8.9Hz,1H),4.60(d,J＝6.0Hz,2H),4.09(s,3H),3.60(dd,J＝10.5,5.7Hz,2H),2.58-2.51(m,2H),2.32(s,6H),1.79(dt,J＝11.5,5.9Hz,2H)； 13CNMR(100MHz,CDCl 3)δ181.01,168.94,154.71，150.18，148.02，147.50，144.16，133.26，131.09，122.31，121.94，121.21，117.00，111.33,107.39,102.87,99.52,59.62,56.28,45.70,45.42,40.68,24.81.
Embodiment 16: the preparation of (compound 16)
Prepare compound 16 according to the step of embodiment 15, difference is: change the 2-picolyl amine in the step 4 in embodiment 15 into 3-picolyl amine and react.The productive rate 56.2% of gained compound 16, fusing point 220-222 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+460.2349, experimental value: 460.2343.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.83(s,1H),11.46(s,1H),8.70(s,1H),8.67(s,1H),8.54(d,J＝3.8Hz,1H),7.91(d,J＝8.1Hz,1H),7.75(d,J＝7.6Hz,1H),7.60(d,J＝8.8Hz,1H),7.30(s,1H),7.17(t,J＝7.9Hz,1H),7.08(d,J＝7.5Hz,1H),6.14(d,J＝8.9Hz,1H),4.59(d,J＝5.3Hz,2H),4.08(s,3H),3.60(d,J＝4.5Hz,2H),2.65-2.55(m,2H),2.38(s,6H),1.86-1.76(m,2H)； 13CNMR(100MHz,CDCl 3)δ180.93,169.06,154.70,149.01,148.84,147.99,144.17,134.84,133.72,133.45,131.05,123.78,122.32,121.16,116.98,111.30,107.33,102.59,99.56,59.17,56.26,45.19,44.32,40.17,24.80.
Embodiment 17: the preparation of (compound 17)
Prepare compound 17 according to the step of embodiment 15, difference is: change the 2-picolyl amine in the step 4 in embodiment 15 into 4-picolyl amine and react.The productive rate 65.8% of gained compound 17, fusing point 212-214 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+460.2349, experimental value: 460.2336.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.84(s,1H),11.62(t,J＝5.8Hz,1H),8.73(s,1H),8.66-8.59(m,1H),7.95(d,J＝8.1Hz,1H),7.64(td,J＝7.7,1.8Hz,1H),7.52(d,J＝8.9Hz,1H),7.41(d,J＝7.9Hz,1H),7.18(dd,J＝15.3,7.5Hz,2H),7.08(dd,J＝7.8,1.0Hz,1H),6.16(d,J＝8.9Hz,1H),4.72(d,J＝5.9Hz,2H),4.08(s,3H),3.59(dd,J＝10.6,5.7Hz,2H),2.58-2.48(m,2H),2.34(s,6H),1.83-1.72(m,2H)； 13CNMR(100MHz,CDCl 3)δ180.93,169.05,158.22,154.85,149.46,147.99,144.23,136.94,133.28,131.09,122.38,122.21,121.06,121.02,117.10,111.21,107.40,102.41,99.87,59.67,56.25,48.69,45.44,40.69,24.88.
Embodiment 18: the preparation of (compound 18)
Compound 18 is prepared according to the step of embodiment 15, difference is: the 2-picolyl amine in the step 4 in embodiment 15 is changed into two (2-pyridyl) methylamine and react, the productive rate 39.9% of gained compound 18, fusing point 90-92 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+551.2771, experimental value: 551.2793.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.55(s,1H),8.85(s,1H),8.50(d,J＝4.4Hz,2H),7.96(d,J＝8.0Hz,1H),7.63-7.54(m,4H),7.52(d,J＝8.8Hz,1H),7.16(t,J＝7.9Hz,1H),7.13-6.99(m,3H),6.60(d,J＝8.7Hz,1H),4.73(s,4H),4.07(s,3H),3.58(d,J＝4.8Hz,2H),2.58-2.46(m,2H),2.29(s,6H),1.82-1.65(m,2H)； 13CNMR(100MHz,CDCl 3)δ177.70,168.66,158.47,154.59,148.94,147.87,144.89,136.80,131.35,130.66,123.38,122.81,122.03,120.88,117.76,112.91,111.17,109.20,108.00,59.75,59.47,56.24,45.41,40.68,24.86。
Embodiment 19: the preparation of (compound 19)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-methoxybenzoic acid is prepared according to step 1 in embodiment 11;
2,1-chloro-5-methoxyl-9-oxo-9,10-acridan-4-carboxylic acid is prepared according to step 2 in embodiment 11;
3,1-chloro-N-(2-methoxy ethyl)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By the 1-chloro-5-methoxyl-9-oxo-9 obtained in step 2,10-acridan-4-carboxylic acid (0.5g, 1.74mmol) be slowly added dropwise to N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (0.42g, 2.61mmol) (DMF, 10.00ml), in stirring at room temperature 30 minutes after dropwising, then 2-methoxyethyl amine (0.39g, 5.22mmol) is added in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, i.e. the chloro-N-of 1-(2-methoxy ethyl)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 57.4%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ12.75(s,1H),7.96(d,J＝8.0Hz,1H),7.72(d,J＝8.2Hz,1H),7.22-7.15(m,2H),7.11(dd,J＝7.8,1.1Hz,1H),6.82(s,1H),4.08(s,3H),3.74(dd,J＝10.3,5.1Hz,2H),3.67-3.61(m,2H),3.43(s,3H).
4, the preparation of compound 19
By the chloro-N-of 1-(2-the methoxy ethyl)-5-methoxyl group-9-oxo-9 obtained in step 3; 10-dihydropyridine-4-acid amides (0.10g; 0.28mmol) be dissolved in 2-picolyl amine (2.00mL), reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 19 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 83.5%, fusing point 218-220 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+433.1876, experimental value: 433.1862.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.48(s,1H),11.65(s,1H),8.64(d,J＝4.6Hz,1H),7.95(d,J＝7.9Hz,1H),7.66(t,J＝7.1Hz,1H),7.60(d,J＝8.9Hz,1H),7.40(d,J＝7.7Hz,1H),7.20(dd,J＝16.1,7.9Hz,2H),7.09(d,J＝7.7Hz,1H),6.47(s,1H),6.17(d,J＝8.9Hz,1H),4.73(d,J＝5.5Hz,2H),4.08(s,3H),3.67(d,J＝4.9Hz,2H),3.58(d,J＝4.8Hz,2H),3.39(s,3H)； 13CNMR(100MHz,CDCl 3)δ180.90,168.95,157.96,155.13,149.28,147.90,144.11,137.15,133.37,130.97,122.45,122.32,121.22,121.16,117.15,111.35,107.36,101.97,99.93,71.29,58.88,56.29,48.56,39.35.
Embodiment 20: the preparation of (compound 20)
Prepare compound 20 according to the step of embodiment 19, difference is: change the 2-picolyl amine in the step 4 in embodiment 19 into 3-picolyl amine and react.The productive rate 75.2% of gained compound 20, fusing point 252-253 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+433.1876, experimental value: 433.1881.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.49(s,1H),11.51(t,J＝5.6Hz,1H),8.67(s,1H),8.55(s,1H),7.92(d,J＝8.0Hz,1H),7.76(d,J＝7.8Hz,1H),7.60(d,J＝8.9Hz,1H),7.30(dd,J＝7.8,4.8Hz,1H),7.19(t,J＝8.0Hz,1H),7.09(d,J＝7.0Hz,1H),6.47(s,1H),6.13(d,J＝8.9Hz,1H),4.60(d,J＝5.7Hz,2H),4.08(s,3H),3.68(dd,J＝10.2,5.0Hz,2H),3.61-3.54(m,2H),3.40(s,3H)； 13CNMR(100MHz,CDCl 3)δ180.91,168.88,154.93,148.76,148.64,147.92,144.06,135.04,133.37,130.95,123.86,122.39,121.35,117.03,111.42,107.32,102.29,99.55,71.25,58.89,56.30,44.33,39.36.
Embodiment 21: the preparation of (compound 21)
Prepare compound 21 according to the step of embodiment 19, difference is: change the 2-picolyl amine in the step 4 in embodiment 19 into 4-picolyl amine and react.The productive rate 79.3% of gained compound 21, fusing point 235-236 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+433.1876, experimental value: 433.1881.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.48(s,1H),11.56(t,J＝5.7Hz,1H),8.57(d,J＝5.1Hz,2H),7.94(d,J＝8.2Hz,1H),7.58(d,J＝8.9Hz,1H),7.34(d,J＝5.2Hz,2H),7.19(d,J＝8.0Hz,1H),7.10(d,J＝7.8Hz,1H),6.48(s,1H),6.01(d,J＝8.9Hz,1H),4.60(d,J＝5.9Hz,2H),4.09(s,3H),3.67(dd,J＝10.0,5.1Hz,2H),3.57(t,J＝4.9Hz,2H),3.39(s,3H)； 13CNMR(100MHz,CDCl 3)δ180.97,168.84,154.95,149.78,147.94,144.04,133.33,130.99,122.40,122.06,121.39,117.08,111.50,102.55,99.57,71.25,58.85,56.30,45.74,39.37.
Embodiment 22: the preparation of (compound 22)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-methoxybenzoic acid is prepared according to step 1 in embodiment 11;
2,1-chloro-5-methoxyl-9-oxo-9,10-acridan-4-carboxylic acid is prepared according to step 2 in embodiment 11;
3,1-chloro-N-(4-(dimethylamino) butyl)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By the 1-chloro-5-methoxyl-9-oxo-9 obtained in step 2,10-acridan-4-carboxylic acid (0.5g, 1.65mmol) is slowly added dropwise to N, N '-carbonyl dimidazoles (0.40g, (DMF in dimethyl formamide solution 2.48mmol), 10.00ml), in stirring at room temperature 30 minutes after dropwising, then by N, N-dimethyl-1,4-butanediamine (0.58g, 4.95mmol) adds in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, i.e. the chloro-N-of 1-(4-(dimethylamino) butyl)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 47.8%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ12.97(s,1H),9.16(s,1H),7.92(d,J＝8.1Hz,1H),7.73(d,J＝8.2Hz,1H),7.15(t,J＝8.0Hz,1H),7.07(d,J＝8.0Hz,2H),4.05(s,3H),3.50-3.40(m,2H),2.34(t,J＝6.2Hz,2H),2.19(s,6H),1.78(dt,J＝12.2,6.2Hz,2H),1.72-1.60(m，2H).
4, the preparation of compound 22
By the chloro-N-of 1-(4-(dimethylamino) the butyl)-5-methoxyl group-9-oxo-9 obtained in step 3; 10-dihydropyridine-4-acid amides (0.11; 0.28mmol) be dissolved in 4-picolyl amine (2.00mL); reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 22 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 65.8%, fusing point 212-214 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+474.2505, experimental value: 474.2495.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.86(s,1H),11.26(t,J＝5.8Hz,1H),8.54(d,J＝4.0Hz,2H),8.43(s,1H),7.98(d,J＝9.0Hz,1H),7.77(d,J＝7.9Hz,1H),7.39(d,J＝5.2Hz,2H),7.32(d,J＝7.5Hz,1H),7.21(t,J＝8.0Hz,1H),6.22(d,J＝9.0Hz,1H),4.69(d,J＝5.8Hz,2H),4.04(s,3H),3.30-3.20(m,2H),2.21(t,J＝7.0Hz,2H),2.11(s,6H),1.54(dd,J＝14.2,7.1Hz,2H),1.46(dd,J＝14.2,7.4Hz,2H)； 13CNMR(100MHz,DMSO-d 6)δ180.11,168.86,154.46,150.26,148.33,147.95,143.90,135.03,130.75,122.66,122.04,121.79,116.97,112.81,106.82,102.59,100.24,59.31,56.86,45.61,45.17,27.50,25.10。
Embodiment 23: the preparation of (compound 23)
Prepare compound 23 according to the step of embodiment 15, difference is: change the 2-picolyl amine in the step 4 in embodiment 15 into 4-pyridine ethyl amine and react.The productive rate 25.4% of gained compound 23, fusing point 208-210 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+460.2349, experimental value: 460.2362.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.57(s,1H),11.17(s,1H),8.54(d,J＝5.7Hz,2H),7.90(d,J＝8.1Hz,1H),7.78(d,J＝8.9Hz,1H),7.23(d,J＝5.6Hz,2H),7.17(t,J＝8.0Hz,1H),7.13(s,1H),7.07(d,J＝7.7Hz,1H),6.23(d,J＝8.9Hz,1H),4.07(s,3H),3.65-3.55(m,4H),3.06(t,J＝7.3Hz,2H),2.72-2.61(m,2H),2.39(s,6H)； 13CNMR(100MHz,CDCl 3)δ180.74,169.16,155.02,149.98,147.99,147.91,144.26,133.83,130.97,124.10,122.44,121.14,117.12,111.34,106.99,101.62,99.03,58.11,56.26,44.96,43.23,36.51,34.73。
Embodiment 24: the preparation of (compound 24)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino) phenylformic acid is prepared
At dimethyl formamide (DMF, 2 are added 50.00ml), 4-dichlorobenzoic acid (0.61g, 4.05mmol), 2-benzaminic acid (0.72g, 5.26mmol), salt of wormwood (1.12g, 8.10mmol) with copper powder (0.13g, 2.03mmol), then stir at 130 DEG C and spend the night, then join in 200ml water after obtained reaction mixture being cooled, the mixture hydrochloric acid obtained is adjusted to pH value and is about 3, suction filtration by dry for the precipitation that obtains, obtain faint yellow solid, i.e. 2-((2-carbonyl-5-chloro-phenyl-) is amino) phenylformic acid, productive rate 10.3%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.20(s,2H),10.93(s,1H),7.92(t,J＝7.8Hz,2H),7.58-7.50(m,2H),7.38(s,1H),7.09-7.03(m,1H),6.95(d,J＝7.8Hz,1H).
2,1-chloro-9-oxo-9,10-acridan-4-carboxylic acid is prepared
By 2-((2-carbonyl-5-chloro-phenyl-) the is amino) phenylformic acid (0.35g obtained in step 1,1.19mmol) join in the vitriol oil (10.00ml), in 80 DEG C of backflows 5 hours, then slowly join in frozen water (50mL) after obtained reaction solution being cooled, be adjusted to pH value by NaOH solution subsequently and be about 5, mixed solution continued stirring at room temperature after 30 minutes, had a large amount of Precipitation.Suction filtration also by dry for the precipitation obtained, obtains pressed powder, i.e. 1-chloro-9-oxo-9,10-acridan-4-carboxylic acid.Productive rate 35.0%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ12.66(s,1H),8.29(d,J＝8.2Hz,1H),8.18(d,J＝8.5Hz,1H),7.75(t,J＝7.4Hz,1H),7.66(d,J＝8.2Hz,1H),7.34-7.28(m,2H).
3,1-chloro-N-(2-(dimethylamino) ethyl)-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By the chloro-9-oxo-9 of 1-obtained in step 2,10-acridan-4-carboxylic acid (2.0g, 7.33mmol) is slowly added dropwise to N, N '-carbonyl dimidazoles (1.78g, (DMF in dimethyl formamide solution 10.99mmol), 10.00ml), in stirring at room temperature 30 minutes after dropwising, then by N, N-dimethyl-1,2-quadrol (1.90g, 21.99mmol) adds in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, i.e. the chloro-N-of 1-(2-(dimethylamino) ethyl)-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 40.5%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.12(s,1H),8.55(s,1H),8.32(d,J＝8.0Hz,1H),8.24(d,J＝9.0Hz,1H),7.58(t,J＝7.7Hz,1H),7.32(d,J＝8.0Hz,1H),7.21(t,J＝7.5Hz,1H),6.62(d,J＝8.9Hz,1H),3.95-3.85(m,J＝4.5Hz,2H),3.35-3.25(m,J＝4.7Hz,2H),2.89(s,6H).
4, the preparation of compound 24
By the chloro-N-of 1-(2-(dimethylamino) the ethyl)-9-oxo-9 obtained in step 3; 10-dihydropyridine-4-acid amides (0.096g; 0.28mmol) be dissolved in 4-picolyl amine (2.00mL); reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 24 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 10.3%, high resolution mass spectrum (ESI): calculated value [M+H]+416.2087, experimental value: 416.2097.
Compound structure confirmation data are:
1HNMR(400MHz,MeOD)δ8.50(d,J＝6.0Hz,2H),8.30(d,J＝8.1Hz,1H),7.91(d,J＝9.0Hz,1H),7.72(t,J＝7.1Hz,1H),7.51-7.48(m,2H),7.47(s,1H),7.30(t,J＝7.9Hz,1H),6.22(d,J＝9.1Hz,1H),4.80-4.70(m,2H),3.56(t,J＝6.8Hz,2H),2.66(t,J＝6.6Hz,2H),2.38(s,6H)。
Embodiment 25: the preparation of (compound 25)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-trifluoromethylbenzoic acid is prepared
At dimethyl formamide (DMF, 2 are added 50.00ml), 4-dichlorobenzoic acid (0.61g, 4.05mmol), 2-amino-3-trifluoromethylbenzoic acid (1.08g, 5.26mmol), salt of wormwood (1.12g, 8.10mmol) with copper powder (0.13g, 2.03mmol), then stir at 130 DEG C and spend the night, then join in 200ml water after obtained reaction mixture being cooled, the mixture hydrochloric acid obtained is adjusted to pH value and is about 3, suction filtration by dry for the precipitation that obtains, obtain faint yellow solid, i.e. 2-((2-carbonyl-5-chloro-phenyl-) is amino)-3-trifluoromethylbenzoic acid, productive rate 67.1%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.30(s,2H),9.85(s,1H),8.09(d,J＝7.3Hz,1H),8.04(d,J＝7.9Hz,1H),7.87(d,J＝8.5Hz,1H),7.63(t,J＝7.8Hz,1H),6.78(dd,J＝8.5,1.9Hz,1H),6.25(d,J＝1.9Hz,1H).
2, the chloro-5-trifluoromethyl of 1--9-oxo-9,10-acridan-4-carboxylic acid is prepared
By 2-((2-carbonyl-5-chloro-phenyl-) the is amino)-3-trifluoromethylbenzoic acid (0.43g obtained in step 1,1.19mmol) join in the vitriol oil (10.00ml), in 80 DEG C of backflows 5 hours, then slowly join in frozen water (50mL) after obtained reaction solution being cooled, be adjusted to pH value by NaOH solution subsequently and be about 5, mixed solution continued stirring at room temperature after 30 minutes, had a large amount of Precipitation.Suction filtration also by dry for the precipitation obtained, obtains pressed powder, i.e. the chloro-5-trifluoromethyl of 1--9-oxo-9,10-acridan-4-carboxylic acid.Productive rate 85.6%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.24(s,1H),8.36(d,J＝7.5Hz,1H),8.24(d,J＝8.0Hz,1H),8.06(d,J＝7.0Hz,1H),7.38(t,J＝7.2Hz,1H),7.28(d,J＝8.0Hz,1H).
3,1-chloro-N-(2-(dimethylamino) ethyl)-5-trifluoromethyl-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By the chloro-5-trifluoromethyl of the 1--9-oxo-9 obtained in step 2,10-acridan-4-carboxylic acid (0.7g, 2.05mmol) is slowly added dropwise to N, N '-carbonyl dimidazoles (0.50g, (DMF in dimethyl formamide solution 3.08mmol), 10.00ml), in stirring at room temperature 30 minutes after dropwising, then by N, N-dimethyl-1,2-quadrol (0.54g, 6.16mmol) adds in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, i.e. the chloro-N-of 1-(2-(dimethylamino) ethyl)-5-trifluoromethyl-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 43.9%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.58(s,1H),8.62(d,J＝8.0Hz,1H),7.97(d,J＝7.5Hz,1H),7.80(d,J＝8.3Hz,1H),7.33(t,J＝7.7Hz,2H),7.24(d,J＝8.0Hz,1H),3.65-3.55(m,2H),2.60(t,J＝5.8Hz,2H),2.32(s,6H).
4, the preparation of compound 25
By the chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-trifluoromethyl-9-oxo-9 obtained in step 3; 10-dihydropyridine-4-acid amides (0.16g; 0.28mmol) be dissolved in 4-picolyl amine (2.00mL); reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 25 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 18.2%, fusing point 178-180 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+484.1960, experimental value: 484.1940.
Compound structure confirmation data are:
1HNMR(400MHz,MeOD)δ8.58(d,J＝8.2Hz,1H),8.50(d,J＝5.9Hz,2H),8.05(d,J＝7.5Hz,1H),7.93(d,J＝9.0Hz,1H),7.49(d,J＝5.4Hz,2H),7.38(t,J＝7.9Hz,1H),6.28(d,J＝9.1Hz,1H),4.73-4.76(m,2H),3.56(t,J＝6.7Hz,2H),2.64(t,J＝6.6Hz,2H),2.37(s,6H). 19FNMR(376MHz,DMSO-d 6)δ-61.63。
Embodiment 26: the preparation of (compound 26)
1,2-((2-carbonyl-5-chloro-phenyl-) is amino)-3,5-dichlorobenzoic acids are prepared
At dimethyl formamide (DMF, 2 are added 50.00ml), 4-dichlorobenzoic acid (0.61g, 4.05mmol), 2-amino-3, 5-dichlorobenzoic acid (1.08g, 5.26mmol), salt of wormwood (1.12g, 8.10mmol) with copper powder (0.13g, 2.03mmol), then stir at 130 DEG C and spend the night, then join in 200ml water after obtained reaction mixture being cooled, the mixture hydrochloric acid obtained is adjusted to pH value and is about 3, suction filtration by dry for the precipitation that obtains, obtain faint yellow solid, i.e. 2-((2-carbonyl-5-chloro-phenyl-) is amino)-3, 5-dichlorobenzoic acid, productive rate 45.6%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.36(s,2H),10.10(s,1H),7.99(d,J＝2.4Hz,1H),7.89(d,J＝8.5Hz,1H),7.86(d,J＝2.4Hz,1H),6.85(dd,J＝8.5,1.9Hz,1H),6.34(d,J＝1.8Hz,1H).
2,1,5,7-tri-chloro-9-oxo-9,10-acridan-4-carboxylic acid is prepared
By the 2-((2-carbonyl-5-chloro-phenyl-) is amino)-3 obtained in step 1,5-dichlorobenzoic acid (0.43g, 1.19mmol) join in the vitriol oil (10.00ml), in 80 DEG C of backflows 5 hours, then slowly join in frozen water (50mL) after obtained reaction solution being cooled, be adjusted to pH value by NaOH solution subsequently and be about 5, mixed solution continued stirring at room temperature after 30 minutes, had a large amount of Precipitation.Suction filtration also by dry for the precipitation obtained, obtains pressed powder, i.e. 1,5,7-tri-chloro-9-oxo-9,10-acridan-4-carboxylic acid.Productive rate 90.5%.
Compound structure confirmation data are:
1HNMR(400MHz,DMSO-d 6)δ13.60(s,1H),8.30(s,1H),8.13-8.04(m,2H),8.02(s,1H),7.35-7.33(m,1H).
3,1,5,7-tri-chloro-N-(2-(dimethylamino) ethyl)-9-oxo-9,10-dihydropyridine-4-acid amides is prepared
By 1,5, the 7-tri-chloro-9-oxo-9 obtained in step 2,10-acridan-4-carboxylic acid (0.8g, 2.35mmol) is slowly added dropwise to N, N '-carbonyl dimidazoles (0.57g, (DMF in dimethyl formamide solution 3.52mmol), 10.00ml), in stirring at room temperature 30 minutes after dropwising, then by N, N-dimethyl-1,2-quadrol (0.62g, 7.04mmol) adds in reaction system, stirred overnight at room temperature.After reaction terminates, extract with methylene dichloride (50mL), gained organic phase washed with water (40mL) washes three times, dry organic phase, be spin-dried for, gained residue obtains pressed powder through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying, namely 1, the chloro-N-of 5,7-tri-(2-(dimethylamino) ethyl)-9-oxo-9,10-dihydropyridine-4-acid amides.Productive rate 49.2%.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ13.43(s,1H),8.28(d,J＝2.3Hz,1H),7.83(d,J＝8.3Hz,1H),7.72(d,J＝2.3Hz,1H),7.39(d,J＝8.3Hz,1H),7.25(s,1H),3.60(dd,J＝10.0,5.2Hz,2H),2.68-2.56(m,2H),2.33(s,6H).
4, the preparation of compound 26
To obtain in step 31; 5; the chloro-N-of 7-tri-(2-(dimethylamino) ethyl)-9-oxo-9; 10-dihydropyridine-4-acid amides (0.16g; 0.28mmol) be dissolved in 4-picolyl amine (2.00mL); reaction system, under argon shield, is spent the night in 90 DEG C of stirrings.After reaction terminates, reaction solution is cooled to room temperature, add methylene dichloride (50.00mL) and water (50.00mL), after extraction, gained organic phase uses water (40mL) to wash three times again, dry organic phase, be spin-dried for, gained residue obtains yellow solid powder, i.e. compound 26 through column chromatography (eluent: ethyl acetate/ethanol (9:1v/v)) purifying.Productive rate 28.1%, fusing point 114-116 DEG C, high resolution mass spectrum (ESI): calculated value [M+H]+484.1307, experimental value: 484.1317.
Compound structure confirmation data are:
1HNMR(400MHz,CDCl 3)δ14.01(s,1H),11.23(s,1H),8.57(d,J＝5.7Hz,2H),8.23(d,J＝2.2Hz,1H),7.74(d,J＝9.0Hz,1H),7.69(d,J＝2.2Hz,1H),7.46(s,1H),7.29(d,J＝5.5Hz,2H),6.04(d,J＝9.0Hz,1H),4.56(d,J＝5.6Hz,2H),3.64(d,J＝5.2Hz,2H),2.80-2.70(m,2H),2.44(s,6H)； 13CNMR(100MHz,CDCl 3)δ179.31,168.83,150.25,146.97,134.12,132.69,126.89,124.38,123.30,122.58,121.83,106.88,100.64,57.62,45.73,44.84,36.53.
Embodiment 27:MTT method cell inhibitory effect screening active ingredients
Pass through mtt assay, adopt human chronic myelogenous leukemia (CML) cell line k562, detect the body outer cell proliferation inhibit activities of the compound that embodiment 1-26 prepares, wherein, K562 is suspension cell, with being the RPIM-1640 nutrient solution of 10% foetal calf serum containing volume fraction, in 37 DEG C, volume fraction is the CO of 5% 2cellar culture under condition; Detect the solid tumor cell in-vitro multiplication inhibit activities of the compound 3 that embodiment 3 prepares, HepG2, RPMI-1640, MCF-7, CNE-2, A375, A172andU118-MG are adherent growth cell, with being the DMEM nutrient solution of the foetal calf serum of 10% containing volume fraction, in 37 DEG C, volume fraction is the CO of 5% 2cellar culture under condition; NCI-H520 and Hela cell is adherent growth cell, with being the RPMI-1640 nutrient solution of the foetal calf serum of 10% containing volume fraction, in 37 DEG C, volume fraction is the CO of 5% 2cellar culture under condition; U251 cell is adherent growth cell, with being the MEM-EBSS nutrient solution of the foetal calf serum of 10% containing volume fraction, in 37 DEG C, volume fraction is the CO of 5% 2cellar culture under condition.
Concrete operations are as follows:
First, the compound (i.e. sample) prepared by embodiment 1-26 is mixed with DMSO (dimethyl sulfoxide (DMSO)) solution that compound concentration is 5mM/L respectively, then by obtain solution through gradient dilution, obtain the sample solution of a series of concentration gradient.
Then, the K562 cell in vegetative period of taking the logarithm, with 1.5 × 10 5the cell density of individual/mL is inoculated in 96 orifice plates, 99 μ L/ holes, and then every hole adds sample solution 1 μ L, makes sample effect final concentration be respectively 0.1 μM, 1 μM, 5 μMs, 10 μMs, 25 μMs and 50 μMs.Often kind of sample, each concentration establish three multiple holes, and arrange a positive control and blank, wherein, positive controls add positive control medicine cis-platinum with the solution of sample solution with concentration, blank group does not add sample solution.MTT solution is added after effect 48h, 10 μ L/ holes, continue cultivation after 4 hours, in 2000rpm, at 4 DEG C centrifugal 5 minutes, dimethyl sulfoxide (DMSO) (DMSO) is added after sucking supernatant, 100 μ L/ holes, in 37 DEG C of insulations about 10 minutes, then with micro oscillator vibration about 5 minutes, make dissolving crystallized complete, OD value is measured in 490nm place by microplate reader, be calculated as follows cell proliferation inhibition rate (InhibitionRate, IR%): IR%=(positive control OD-sample OD)/(positive control OD-blank OD) × 100%, experimental result is in table 1 and table 2.
The body outer cell proliferation inhibit activities of the compound that single pyridine amine that table 1 synthesizes replaces
Note: IC 50represent half-inhibition concentration.
The body outer cell proliferation inhibit activities of the compound that the two pyridine amine showing 2-in-1 one-tenth replace
Note: IC 50represent half-inhibition concentration.
The NCI-H520 taken the logarithm vegetative period, U251, A375, A172, Hela, CNE-2, U118-MG, HepG2 and MCF-7 solid tumor cell, with 6 × 10 3the cell density of individual/mL is inoculated in 96 orifice plates, 99 μ L/ holes, in 37 DEG C, and the CO of 5% 2about 12 hours are cultivated under condition.Then every hole adds compound 3 solution 1 μ L, makes compound 3 act on final concentration and is respectively 0.1 μM, 1 μM, 5 μMs, 10 μMs, 25 μMs and 50 μMs.Each concentration establishes three multiple holes, and arranges blank, and wherein blank group does not add sample solution.MTT solution is added after effect 48h, 10 μ L/ holes, continue cultivation after 4 hours, dimethyl sulfoxide (DMSO) (DMSO) is added after sucking supernatant, 100 μ L/ holes, in 37 DEG C of insulations about 10 minutes, then with micro oscillator vibration about 5 minutes, make dissolving crystallized complete, OD value is measured in 490nm place by microplate reader, be calculated as follows cell proliferation inhibition rate (InhibitionRate, IR%): IR%=(positive control OD-sample OD)/(positive control OD-blank OD) × 100%, experimental result is in table 3.
The compound 3 that table 3 synthesizes is for the in-vitro multiplication inhibit activities of multiple solid tumor cell
Note: IC 50represent half-inhibition concentration.
Can find out that from table 1 and table 2 activity of the difference of dihydroketoacridine ring substituents on compound has to affect significantly.First, the long alkyl chains between 4 amido linkages and N, N-dimethyl has material impact to anti-tumor activity, and the compound (n=2) wherein comprising 2 methyl is active best.In addition, (R in the group of 4 amido linkages connections 2substituting group), compound (the such as compound 1) activity that N, N-dimethyl replaces is much better than the compound (such as compound 7) of methoxy substitution.Secondly, studied further by structure activity relationship, find that the place value (2,3,4 replacements) of atom N in pyridine ring is smaller to activity influence.But when introducing two pyridine amine substituting group (such as compound 18) in compound structure, anti-tumor activity more single pyridine amine substitution compound (such as compound 15) has obvious reduction.Again, by replacing (-H) to the nothing of 5 of dihydroketoacridine ring, and introduce different from electronics (methyl, methoxyl group) and electrophilic (trifluoromethyl, 3,5-dichloro) substituted radical, find 5 the highest (such as IC of compound 3 of methyl substituted activity 50value reaches 0.43 μM), the electronic effect and the stereoeffect that indicate 5 bit substituent groups of dihydroketoacridine parent also have impact to anti-tumor activity.
Select from table 1 and table 2 the active best compound 3 (IC of suspension cell K562 cell anti-tumor 50=0.43 μM) test it and whether also have good inhibit activities to solid tumor cell.Can be found out by table 3, compound 3 has good inhibit activities equally for solid tumor cell, such as, for HepG2 cell, and IC 50value can reach 0.25 μM.
Embodiment 28: topoisomerase enzyme test
Utilize each compound shown in table 1 and table 2 to carry out topoisomerase enzyme test, concrete operations are as follows:
By 200ng superhelix pBR322DNA (buying from Takara), 1.0 unit restructuring human DNA topoisomerase I (buying from Takara) and reaction buffer (35mMTris – HCl (pH8.0), 5mMMgCl 272mMKCl, 0.01% bovine serum albumin, 2mM spermidine, 5mM dithiothreitol (DTT)) and testing compound be made into experimental group solution, again by 200ng superhelix pBR322DNA (buying from Takara), 1.0 unit restructuring human DNA topoisomerase I (buying from Takara) and reaction buffer (35mMTris – HCl (pH8.0), 5mMMgCl 272mMKCl, 0.01% bovine serum albumin, 2mM spermidine, 5mM dithiothreitol (DTT)) and DMSO (dimethyl sulfoxide (DMSO)) be made into the first control group solution, and by 200ng superhelix pBR322DNA (buying from Takara) and reaction buffer (35mMTris – HCl (pH8.0), 5mMMgCl 272mMKCl, 0.01% bovine serum albumin, 2mM spermidine, 5mM dithiothreitol (DTT)) be made into the second control group solution, then by experimental group solution, the first control group solution and the second control group solution, at 37 DEG C, 30 minutes are hatched respectively, then electrophoretic separation in the sepharose of 1%, 100V electrophoresis 25 minutes, after electrophoresis, gel is dyeed 10 minutes in ethidium bromide solution, subsequently in gel imaging system, observe under ultraviolet transmission lamp and take pictures.Part of test results is shown in Fig. 1, wherein, R represents relax, namely DNA is in relaxed state, S represents supercoil, namely DNA is in superhelix state, and in Fig. 2 a, the concentration that swimming lane 1-17 is respectively the second control group solution, the first control group solution and compound 1-15 is the electrophoresis detection result of the experimental group solution of 50 μMs; In Fig. 2 b, the concentration that swimming lane 1-13 is respectively the second control group solution, the first control group solution and compound 16-26 is the electrophoresis detection result of the experimental group solution of 50 μMs;
DNA original state is superhelix state, and after adding topoisomerase, superhelix is untwisted and become relaxed state, and if the compound simultaneously added can suppress topoisomerase with topoisomerase enzyme interacting, then DNA still can be in superhelix state.From the result of Fig. 2 a and Fig. 2 b, compound 1-6, compound 11-17 and compound 22-26 all can play the effect suppressing topoisomerase.
Embodiment 29:DNA connects experiment
The interaction mode of Medicine small molecule and DNA is mainly divided into intercalation (between two pairs of base pairs of drug molecule plane intercalation of DNA inside and form π-π between base team interact), groove contact (the non-bonding effect such as groove generation hydrogen bond of drug molecule and DNA outside) and electrostatic interaction.Dihydroketoacridine loop section in compound of the present invention can be interacted to there is π-π by intercalation mode and DNA internal base.In the present embodiment, for compound 3 shown in table 1, carry out DNA and connect experiment, specific as follows:
It is in the Tris-HCl damping fluid of 7.2 that ctDNA (buying in Sigma company) is dissolved in the pH prepared, the purity (A260:A280=1.85) of its ctDNA of determined by ultraviolet spectrophotometry, and calculates the concentration of DNA solution.Adopt BeckmanCoulterDU800 ultraviolet spectrophotometer, spectrophotofluorometer and Pin Shi viscometer measure the combination of compound 3 and ctDNA, specific as follows:
By the DMSO solution of the compound 3 of 20 microlitre 1mM, transfer in the cuvette adding 1950 microliter of buffer liquid (sodium-chlor of Tris and 50mM of 5mM is dissolved in pure water and uses salt acid for adjusting pH to 7.2 simultaneously), then (0 is progressively added successively, 2.5,5,7.5,10,15,20,30 microlitres) the ctDNA solution of 2mM concentration.Hatch 5 minute after needing after adding ctDNA to mix at every turn, then be determined at the absorbancy in 350nm-500nm wavelength region.The like, until finally add the ctDNA of 30 microlitres, mix and measure absorbancy after 5 minutes.Absorbance measurement the results are shown in Figure 3a.
The DMSO solution of the compound 3 of 20 microlitre 1mM, adds in the cuvette having damping fluid (sodium-chlor of Tris and 50mM of 5mM is dissolved in pure water and uses salt acid for adjusting pH to 7.2 simultaneously), makes final compound concentration be 10 μMs, the ctDNA solution of the 2mM concentration then progressively added successively, makes ctDNA final concentration be followed successively by 0,10,20,30,40,50,60,70,80,90 and 100 μMs.Hatch 5 minute after needing after adding ctDNA to mix at every turn, then be determined at the fluorescence intensity (excitation wavelength is set to 425nm) in 450nm-700nm wavelength region, the like.Fluorescent strength determining the results are shown in Figure 3b.
The Tris-HCl solution of ethidium bromide (EB) of 20 microlitre 1mM and the ctDNA solution of 40 microlitres, add in the cuvette having damping fluid (sodium-chlor of Tris and 50mM of 5mM is dissolved in pure water and uses salt acid for adjusting pH to 7.2 simultaneously), make EB final concentration be 10 μMs, ctDNA final concentration is 40 μMs.The DMSO solution of the compound 3 of the 1mM concentration then progressively added successively, makes compound 3 final concentration be followed successively by 0,5,10,20 and 30 μM.Hatch 5 minute after needing after adding compound 3 to mix at every turn, then be determined at the fluorescence intensity (excitation wavelength is set to 366nm) in 450nm-700nm wavelength region, the like.Fluorescent strength determining the results are shown in Figure 3c.
Final concentration, at 25.0 DEG C, is that the ctDNA solution of 200 μMs adds in Pin Shi viscometer by envrionment temperature, the DMSO solution of the compound 3 progressively adding (12-72 microlitre) 2.5mM that then divides into groups, the final concentration of compound 3 is made to be respectively 6,12,18,24,30,36 μMs.The viscosity number that liquid flow time obtains corresponding ctDNA concentration is often organized by measuring.Viscosity measurements is shown in Fig. 3 d.
As can be seen from experimental result, after Fig. 3 a and Fig. 3 b indicates intuitively and add ctDNA in compound 3 solution, the ultraviolet absorptivity of solution has obviously decline and fluorescence intensity to have obvious rising, this shows that ctDNA and compound 3 exist interaction really, and the dihydroketoacridine loop section namely in compound of the present invention can be interacted to there is π-π by intercalation mode and DNA internal base.Fig. 3 c then further shows, along with the concentration of compound 3 increases, the fluorescence intensity of EB progressively reduces.This illustrates that compound 3 to a certain degree can compete the embedded mode of EB and DNA.Also just indicate compound 3 to be combined with DNA by embeddeding action.Find out from Fig. 3 d, viscosity number progressively increases along with compound 3 ratio with DNA, and it is act on DNA by embedded mode that this visual phenomenon indicates compound 3.Utilize other compounds shown in table 1 and table 2 to carry out repeating experiment, obtain the experimental result similar with compound 3.

Claims (9)

1. the compound shown in a formula I or formula II:
In formula I, formula II, R 1for H, OCH 3, OCH 2cH 3, OCH 2cH 2cH 3, Cl, Br, CF 3, NO 2or carbonatoms is the straight chained alkyl of 1-5, R 2for N (CH 3) 2or OCH 3, R 3for 2-pyridyl, 3-pyridyl, 4-pyridyl, indyl, quinolyl, pyrimidyl or pyrazinyl, m=1,2,3 or 4, n=1,2,3 or 4.
2. compound shown in formula I according to claim 1 or formula II, is characterized in that: compound shown in described formula I or formula II be selected from following any one:
3. prepare a method for compound shown in formula I described in claim 1 or formula II, comprise the steps:
1) under condensing agent effect, the compound shown in the compound shown in formula III and formula IV is reacted, obtains the compound shown in formula V;
In formula III, R 1definition and claim 1 in R 1definition identical;
In formula IV, R 2definition and claim 1 in R 2definition identical; The definition of n is identical with the definition of n in claim 1;
In formula V, R 1definition and claim 1 in R 1definition identical; R 2definition and claim 1 in R 2definition identical; The definition of n is identical with the definition of n in claim 1;
2) under protection of inert gas, the compound shown in the compound shown in formula V and formula VI or the compound shown in formula VII are reacted, obtain the nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides shown in formula I or formula II;
In formula VI, R 3definition and claim 1 in R 3definition identical, the definition of m is identical with the definition of m in claim 1.
4. method according to claim 3, it is characterized in that: step 1) in, described condensing agent is selected from following at least one: N, N'-carbonyl dimidazoles, dicyclohexylcarbodiimide, DIC and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide;
Compound shown in described formula IV be selected from following any one:
Described reaction is carried out in organic solvent, and described organic solvent is selected from following at least one: dimethyl formamide, N,N-DIMETHYLACETAMIDE, chloroform, methylene dichloride and acetone;
The mol ratio of the compound shown in the compound shown in described condensing agent and formula III, formula IV is followed successively by 1-4:1-2:1-10;
The temperature of reaction of described reaction is 20-40 DEG C, and the reaction times is 4-12 hour.
5. method according to claim 3, is characterized in that: step 2) in, described rare gas element is selected from following at least one: argon gas and nitrogen;
Compound shown in described formula VI be following any one:
The proportioning of the compound shown in the compound shown in described formula V and formula VI or the compound shown in formula VII is 0.01-2mmol:0.5-5.00mL;
The temperature of reaction of described reaction is 90-110 DEG C, and the reaction times is 10-20 hour.
6. the application of compound shown in claim 1 Chinese style I or formula II in the following product of preparation:
1) topoisomerase enzyme inhibitor;
2) eukaryote tumor cell proliferation inhibitor;
3) tumour medicine is prevented and/or treated.
7. application according to claim 6, is characterized in that:
Described topoisomerase is topoisomerase I;
Described eukaryote is Mammals;
Described tumour cell is cancer cells;
Described cancer cells is leukaemia cancer cell, lung carcinoma cell, human glioma cell, malignant melanoma cell, glioblastoma cells, cervical cancer cell, nasopharyngeal carcinoma cell, liver cancer cell, breast cancer cell, brain cancer cell, pancreatic cancer cell, ovarian cancer cell, uterine cancer cells, testicular cancer cell, skin cancer cell, stomach cancer cell, colon cancer cell, transitional cell bladder carcinoma cell line or rectum cancer cell;
Described leukaemia cancer cell behaviour chronic myeloid leukemia cell line K562;
Described lung carcinoma cell is human lung carcinoma cell NCI-H520;
Described human glioma cell is U251;
Described malignant melanoma cell is A375;
Described glioblastoma cells behaviour glioblastoma cells A172 or human brain astrocytes's blastoma cell U-118MG;
Described cervical cancer cell is Human cervical cancer cell lines Hela;
Described nasopharyngeal carcinoma cell is human nasopharyngeal carcinoma cell line CNE-2;
Described liver cancer cell is HepG2 cell lines;
Described breast cancer cell is human breast cancer cell line Bcap-37;
Described tumour is cancer;
Described cancer is leukemia cancer, lung cancer, malignant melanoma, glioblastoma multiforme, cervical cancer, nasopharyngeal carcinoma, liver cancer, mammary cancer, the cancer of the brain, carcinoma of the pancreas, ovarian cancer, uterus carcinoma, carcinoma of testis, skin carcinoma, cancer of the stomach, colorectal carcinoma, bladder cancer or the rectum cancer.
8. a product, its activeconstituents is compound shown in claim 1 Chinese style I or formula II; Wherein, described product is: 1) topoisomerase enzyme inhibitor; 2) eukaryote tumor cell proliferation inhibitor; 3) medicine of tumour is prevented and/or treated.
9. product according to claim 8, is characterized in that:
Described topoisomerase is topoisomerase I;
Described eukaryote is Mammals;
Described tumour cell is cancer cells;
Described cancer cells is leukaemia cancer cell, lung carcinoma cell, human glioma cell, malignant melanoma cell, glioblastoma cells, cervical cancer cell, nasopharyngeal carcinoma cell, liver cancer cell, breast cancer cell, brain cancer cell, pancreatic cancer cell, ovarian cancer cell, uterine cancer cells, testicular cancer cell, skin cancer cell, stomach cancer cell, colon cancer cell, transitional cell bladder carcinoma cell line or rectum cancer cell;
Described leukaemia cancer cell behaviour chronic myeloid leukemia cell line K562;
Described lung carcinoma cell is human lung carcinoma cell NCI-H520;
Described human glioma cell is U251;
Described malignant melanoma cell is A375;
Described glioblastoma cells behaviour glioblastoma cells A172 or human brain astrocytes's blastoma cell U-118MG;
Described cervical cancer cell is Human cervical cancer cell lines Hela;
Described nasopharyngeal carcinoma cell is human nasopharyngeal carcinoma cell line CNE-2;
Described liver cancer cell is HepG2 cell lines;
Described breast cancer cell is human breast cancer cell line Bcap-37;
Described tumour is cancer;
Described cancer is leukemia cancer, lung cancer, malignant melanoma, glioblastoma multiforme, cervical cancer, nasopharyngeal carcinoma, liver cancer, mammary cancer, the cancer of the brain, carcinoma of the pancreas, ovarian cancer, uterus carcinoma, carcinoma of testis, skin carcinoma, cancer of the stomach, colorectal carcinoma, bladder cancer or the rectum cancer.
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